美国《Science》2014年12月19日推出中医药特刊，刊登我校校长徐安龙的文章，全文如下：

 

 

 

 

 

 

 

Zheng: A systems biology approach to diagnosis and treatments

 

 

 

 

 

 

 

Traditional Chinese medicine (TCM) is an ancient medical practice system which emphasizes regulating the integrity of the human body and its interrelationship with natural environments. As a key concept in TCM, Zheng (meaning syndrome or pattern) is the overall physiological and/or pathological pattern of the human body in response to a given internal and external condition, which usually is an abstraction of internal disharmony defined by a comprehensive analysis of the clinical symptoms and signs gathered by a practitioner using inspection, auscultation, olfaction, interrogation, and palpation of the pulses (1). Correctly identifying the Zheng is fundamental for the diagnosis and treatment of diseases. Moreover, Zheng has been historically applied as the key pathological principle guiding the prescription of herbal formulas (Figure 1).

 

 

 

A lack of research on Zheng has left us with little understanding of its underlying biology or the relationships between different Zhengs, diseases, and drugs. Moreover,there have been attempts to integrate Zheng differentiation with modern biomedical diagnostic methods, though these efforts have not achieved the desired results (2). Many well-known herbal recipes, such as Liu Wei Di Huang Wan and Jin Kui Shen Qi Wan, have long been used for the clinical treatment of Zheng disorders; however, Zheng-guided treatments are still scarce due to the lack of evidence-based interpretations of syndromes and treatment efficacies. Thus,investigating the biological basis of Zhengs from a molecular to systems level is important for advancing the identification and treatment of these syndromes, and for providing more objective and quantitative diagnostic criteria.

 

 

 

 

 

 

 

Zheng-guided disease research

 

 

 

In Western medicine, a disease is a particular abnormal and pathological condition that affects part or all of the human body and is often construed as a medical condition associated with specific symptoms. By contrast, Zheng puts forth a very different definition of a disease and encompasses all of the symptoms a patient presents.

 

 

 

Because of the highly interconnected nature of the human interactome, it is difficult to study different diseases at the molecular level completely independent of one another (3),and this issue also applies to Zhengs. Moreover, Zhengs are dynamic with changing boundaries, overlapping symptoms,and a multiscale nature, which makes them difficult to understand at a biological and mechanistic level. Thus, we propose that a comprehensive Zheng map be constructed that links together all the Zhengs based on their molecular and cellular relationships. Further, we suggest creating the “Zhengome” as a new 'omics field, in which a network is the basic research unit used to investigate the hierarchy present in the human body,from the molecular to the systems level. A comprehensive understanding of the Zhengome requires us to bring together multiple sources of evidence, from shared genes to proteinprotein interactions, shared environmental factors, common treatments, and phenotypic and clinical manifestations, in order to capture the relationships between the different Zhengs.

 

 

 

Zheng uses the Yin-Yang, exterior-interior, cold-heat, and deficiency-excess definitions to describe patients’ conditions,which are then managed by Zheng-specific recipes (Figure 1).Modern 'omics techniques combined with bioinformatics and bionetwork models through a systems biology approach have been applied to investigate the differences between Zhengs and to identify novel biomarkers. For instance, rheumatoid arthritis (RA) patients differentiated on the basis of “hot” and “cold” Zhengs have been shown to be associated with different underlying genomic and metabolomic profiles, with the RA hot group showing more apoptotic activity than the cold group (4). Additionally, Li et al. used a network-based computational model to understand Zheng in the context of the neuro-endocrine-immune network and found that cold and hot Zhengs were closely related to a metabolism-immune imbalance (5). Wang and colleagues investigated the urine

 

 

 

metabolome of patients with jaundice syndrome and its two subtypes of Yang Huang (acute) and Yin Huang (chronic), and identified several biomarker metabolites (6). However, most of the current studies have relied on only one or two approaches for molecular profiling and have lacked an efficient method to integrate data obtained at different 'omic levels.These studies also did not look at combining the analysis of molecular data with clinical variables, possibly missing an opportunity to generate more convincing conclusions. Considering the limitations of past studies, future efforts should integrate an analysis for all levels of 'omics (e.g., genomics,transcriptomics, epigenomics, and proteomics) data from a large number of patient samples for different Zhengs and include an investigation of the prognostic and therapeutic utilities of the data as a whole. Moreover, combining these molecular data with patients’ clinical information could provide evidence-based theoretical interpretations for Zhengs and enable an assessment of Zheng-based therapeutic approaches.

 

 

 

Zhengs may change dynamically during disease progression.Differentiating the specific Zheng involved in each stage of a disease could provide valuable guidance for prescribing a dynamic therapeutic recipe. Using dynamic network modeling, a disease process can be conceptualized as spatio-temporal changes in network structures. The changes associated with a Zheng under dynamic therapy can be used to identify the key factors in the dynamic biological

 

 

 

networks. Appropriate network perturbation models and subsequent robustness and topology analysis could help unveil potential disease-related genes or therapeutic targets involved in a disease’s progression or evolution (7). The relationships between the different aspects of a disease (e.g.,main symptoms versus complications) in a specific Zheng as well as the psychological, social, and even environmental factors should be taken into account during the modeling and simulation process in order to uncover the dynamic nature of complex diseases. Combining a Zhengome approach with dynamic modeling has the potential for establishing an accurate and quantitative Zheng research model, as well as for creating a new system for performing disease research.

 

 

 

 

 

 

 

Zheng-driven drug discovery

 

 

 

Despite considerable progress in genome, transcriptome,proteome, and metabolome-based high throughput screening methods and in rational drug design, drug discovery often encounters considerable costly failures that challenge the fidelity of the modern drug discovery system. Zheng-driven drug discovery has shown tremendous success for traditional drug discovery throughout Chinese medicine’s history.However, since this concept is completely new to Western medicine, it is no easy task to incorporate Zheng-driven drug discovery into modern drug discovery workflows.

 

 

 

Here, we propose the “Zheng to TCM” and “TCM to Zheng” strategies within the framework of systems pharmacology to investigate biological systems and develop new therapeutics(Figure 2). The first strategy, Zheng to TCM, proposes developing a pipeline from Zheng diagnoses to TCM drugs,including differentiating Zhengs, identifying Zheng-related diseases and the associated genes and proteins, reverse targeting of drug effects, constructing and analyzing network/systems, and finally identifying effective herbal medicines (8). In effect, this strategy can be considered a reverse targeting and screening approach that is designed to uncover drugs from natural products that can target multiple Zhengs or related diseases. The goal of this method is to help researchers identify the active components within medicinal plants and multi-ingredient synergistic herbal formulas or drug combinations (9). In fact, this novel strategy has already been successfully applied in a qi-blood study, where we identified the active compounds in the qi-enriching and blood-tonifying herbs, their targets, and the corresponding pathways involved in the treatment of qi and blood deficiency syndromes (8).

 

 

 

The second strategy, TCM to Zheng, consists of a wholesystem evaluation process starting with herbs or herbal formulas and culminating in identifying the Zhengs. This process includes the initial collection and classification of herbal medicines; screening the ingredients for absorption,distribution, metabolism, excretion, and toxicity (ADME/T);performing targeted drug screenings and tissue localization; constructing and analyzing networks; and finally identifying Zhengs/diseases (10). Using this strategy, it is possible to identify novel multitarget drugs in natural products (11). One particularly striking example is the systematic analysis of blood stasis and qi deficiency syndrome in coronary heart disease and the herbal drugs used to treat the syndromes. The results indicate that the herbs for eliminating blood stasis have pharmacological activity that acts to dilate blood vessel, improve the microcirculation, reduce blood viscosity,and regulate blood lipid, while qi-enhancing herbs have the potential for enhancing energy metabolism and anti-inflammatory activity (12). The TCM to Zheng strategy can also help to elucidate the pharmacological effectiveness of herbs and formulas.

 

 

 

In our ongoing work investigating Pi-deficiency syndrome (PDS) in the context of Zheng, we are analyzing patient samples using the sequencing alternative polyadenylation sites (SAPAS) method, RNA sequencing (13), lipid metabolomics,proteomics, and transcriptomics in order to decipher the pathogenesis and complex responses of the human body to PDS. From a drug development perspective, we plan to systematically investigate the Si Jun Zi decoction, a widely used herbal recipe for PDS, within the framework of the “TCM to Zheng” strategy, so as to understand why this recipe can regulate the immune response, stimulate blood circulation,and adjust gastrointestinal digestive functions. Despite the progress in Zheng-guided drug discovery, its future success requires the integration of multidisciplinary technologies,together with further innovations in these technologies, to facilitate the understanding of multifactorial diseases and the development of new therapies.

 

 

 

 

 

 

 

References

 

 

 

1. F. Cheung, Nature 480, S82 (2011).

 

 

 

2. A. Lu, M. Jiang, C. Zhang, K. Chan, J. Ethnopharmacol. 141, 549

 

 

 

(2012).

 

 

 

3. A. L. Barabasi, N. Gulbahce, J. Loscalzo, Nat. Rev. Genet. 12, 56

 

 

 

(2011).

 

 

 

4. H. van Wietmarschen et al., J. Clin. Rheumatol. 15, 330 (2009).

 

 

 

5. S. Li et al., IET Syst. Biol. 1, 51 (2007).

 

 

 

6. X. Wang et al., Mol. Cell. Proteomics 11, 370 (2012).

 

 

 

7. P. Csermely, T. Korcsmaros, H. J. M. Kiss, G. London, R. Nussinov,

 

 

 

Pharmacol. Therapeut. 138, 333 (2013).

 

 

 

8. J. Liu et al., Evid. Based Compl. Alt. Med. 2013, 938764 (2013).

 

 

 

9. P. Li et al., J. Ethnopharmacol. 151, 93 (2014).

 

 

 

10. C. Huang et al., Brief. Bioinform. 15, 710 (2014).

 

 

 

11. C. Zheng et al., Mol. Diversity 18, 621 (2014).

 

 

 

12. W. Zhou, Y. Wang, J. Ethnopharmacol. 151, 66

 

 

 

  

 

 

 

“证”—— 疾病诊疗的系统生物学方法

 

 

 

翻译：林玮涛

 

 

 

    传统中医学是一种古老的医疗实践体系。它强调人体自身的统一性和人与自然环境的统一性。作为中医学的一个重要概念，“证”是人体在特定的内在或外在条件下的生理或病理概括，通常是由中医师将四诊（望、闻、问、切）所收集的资料，包括临床症状和体征，运用中医学理论进行综合分析并概括出来的疾病本质。正确辨证是疾病诊断和治疗的基础。

 

 

 

    在西方医学中，疾病是指一种特定的病理状态，影响着人体的局部或整体，并具有特定的症状。相比之下，“证”是中医对疾病的独特定义，涵括了患者所有的症状。由于人体自身内部的高度统一和谐，从分子水平上完全独立地对不同疾病进行研究是十分困难的。证候的研究亦如此。再者，证候是动态变化并可相互兼夹的。有史以来，“证”一直是中医确定治法、处方遣药的重要准则。证候方面的研究缺乏，使得其潜在的生物学原理及证候、疾病和处方药物之间的联系难以被理解。既往有学者尝试将中医辨证与现代生物医学的诊断方法相结合，但其结果并未尽如人意。许多众所周知的经方，如六味地黄丸、金匮肾气丸，已经久为中医师辨证治病所用，但这类以证候为导向的治疗在证候和疗效方面仍缺乏循证医学依据。从分子水平上多尺度地对“证”的生物学基础进行研究，使其在生物学和机械论的角度上难以被理解。因此，我们提出构想，建立一种综合的证候图，以分子细胞学联系为依据，将所有的“证”联结在一起。另外，我们建议创立名为“证候组学”(Zhengome)的组学新领域，以网状结构为基础单位，从分子水平和系统水平来研究人体的层次结构。全面地理解“证候组学”，需要引入大量的证据来源，从基因共享到蛋白质相互作用、环境因素共享、共同的治疗、临床表现，目的是为把握不同证候之间的关系。“证”通过阴阳、表里、寒热、虚实来描述患者的病理状态，从而为处方遣药提供依据。现代组学技术通过系统生物学的方法，结合生物信息学和生物网络模型，已被应用于证候间的差异性研究和寻找新的生物标记物。例如，有研究显示，辨证为“热证”和“寒证”的类风湿性关节炎患者具有基因和代谢组学上的差异——热证患者的细胞凋亡比寒证患者更活跃。再者，有学者通过采用一种以网状结构为基础的计算模型，从神经-内分泌-免疫的角度理解证候的涵义，结果发现寒证和热证与代谢-免疫失衡密切相关。有人对黄疸患者的尿液代谢组学及“阳黄”(急性)与“阴黄”(慢性)两种分型进行研究，并找出几种生物标志物代谢产物。然而，目前大多数研究仅仅依靠一种或两种指纹图谱技术的方法，而缺乏一种能将来自不同组学的数据整合在一起的方法。这些研究没有将分子水平数据的分析与临床变量结合在一起，由此可能失去了产生更具说服力的结论的机遇。鉴于既往研究的局限性，未来我们需致力于对大量不同证型患者的数据进行各类组学水平的综合分析，并需涵盖疾病预后和治疗工具方面的研究。再者，将患者的临床信息和分子水平数据结合在一起，可以为证候的理论解释提供循证依据。证候可以随着疾病的进展而动态变化。在疾病的各个不同阶段进行正确辨证，能为及时调整方药提供有利依据。采用动态的网状结构模型，疾病病程可以被定位为网状结构中的时空变化。

 

 

 

    动态调整处方治疗后所发生的证候变化可用于辨别动态生物网状结构中的重要因素。正确的网络微扰模型和稳健性及拓扑分析可以揭示疾病进展或演变潜在的相关基因和治疗靶点。在建立模型和模型的过程中，需将疾病在特定证候中不同方面的表现（例如主症和并发症）、心理因素、社会因素和环境因素之间的关系考虑在内，旨在揭示复杂疾病的动态属性。“证候组学”与动态模型的结合，对建立精准量化的证候研究模型、创立新的疾病研究系统有着潜在意义。

 

 

 

    尽管基因组学、转录组学、蛋白质组学和代谢组学已取得较大进展，合理的药物设计和新药研发仍经常遭遇失败，耗费巨大，阻碍着现代药物的研发。

 

 

 

    纵观中医药发展史，在传统药物的研发中，以证候为导向的药物研发取得了巨大的成就。但是这对于西方医学来说是一种全新的模式。因此，如何将以证候为导向的药物研发融入到现代药物研发的潮流中，将是一大难题。在此，我们提出在系统药理学框架中建立“从证到中医”和“从中医到证”的策略，旨在研究生物系统和开发新型的治疗方法。 “从证到中医”为从证候的诊断到中药处方之间提供了渠道，包括证候的辨别、证候和相关的基因、蛋白及药效反向定位的识别、网状结构系统的构建与分析和最终找出有效的中药疗法。实际上，这样的策略可作为一种反向定位和筛选的途径，从适用于多种证型及相关疾病的天然药物中寻找并研发新药，目的是为了帮助研究者找出药用植物、多成分中药处方或复方合剂的活性成分。而这种新策略已经成功应用于我们的一个研究中。我们在补益气血的中药中找到其有效成分、靶点及在治疗气血不足证中的作用途径。“从中医到证”是指从中药或中药复方到证候辨别的整个系统评估的过程，包括中药的采集与分类，药物吸收、分布、代谢、排泄和具有毒性的成分，药物靶向的检查和组织定位，构建和分析网状结构系统，最终辨别证候/疾病。这种策略可能有助于在天然药物中找出新型的多靶点药物。举个非常显著的例子，就是冠心病气虚血瘀证和相应辨证用药的系统分析，结果提示该类用药中的活血药具有扩张血管、改善循环、降低血液粘度、调节血脂的作用，而补气药具有促进能量代谢和抗炎的疗效。“从中医到证”的策略有助于阐释中药及其复方的药理学作用。在我们正在开展的“脾虚证”研究中，我们采用SAPAS、RNA测序、脂类代谢组学、蛋白质代谢组学和转录组学的方法对患者提供的标本进行分析，以解释脾虚证的发病机制和人体复杂反应。

 

 

 

    我们准备根据“从中医到证”的策略，从药物研发的角度，系统地研究广泛用于治疗脾虚证的四君子汤，目的在于探讨此方为何能够调节免疫反应、促进血液循环和改善胃肠道功能。尽管以证候为导向的药物研发已经取得一定进展，但其未来的发展仍需要多学科技术的结合和创新。这将促进对疾病的多因素理解和新型疗法的发展。

 

 

 

 

 

 

美国Science期刊于1880年由著名发明家爱迪生投资1万美元创办，1894年成为美国最大的科学团体“美国科学促进会”(AAAS)的官方非盈利性刊物。

 

 

 

（宣传部）